The present invention relates to a stereoselective synthesis of leukotriene antagonists. More Particularly, this invention relates to the stereoselective synthesis of (.beta.S,.gamma.R) and (.beta.R,.gamma.S)-4-(3-(4-acetyl-3-hydroxy-2-propyl(phenoxy)propyl)-thio) -.gamma.-hydroxy-.beta.-methylbenzenebutanoic acid, and related compounds. These compounds are useful therapeutic agents for treating allergic conditions, asthma, cardiovascular disorders, inflammation and pain in mammals, especially humans. The compounds are also useful for inducing cytoprotection in mammals, especially humans.
The leukotrienes are a novel group of biologically active mediators derived from arachidonic acid through the action of lipoxygenase enzyme systems. There are two groups of leukotrienes derived from the common unstable precursor Leukotriene A.sub.4. The first of these are the peptido-lipid leukotrienes, the most important being Leukotrienes C.sub.4 and D.sub.4 These compounds collectively account for the biologically active material known as the slow reacting substance of anaphylaxis. See for example, Kreutner, W., et al., Ann. Rpts. Med. Chem., 19, 241 (1984).
The leukotrienes are potent smooth muscle contracting agents, particularly on respiratory smooth muscle but also on other tissues (e.g., gall bladder). In addition, they promote mucous production, modulate vascular permeability changes, and are potent inflammatory agents in human skin. The most important compound in the second group of leukotrienes is Leukotriene B.sub.4, a dihydroxy fatty acid. This compound is a potent chemotactic agent for neutrophils and eosinophils and in addition, may modulate a number of other functions of these cells. It also affects other cell types such as lymphocytes and, for example, may modulate the action of T-suppressor cells and natural killer cells. When injected in vivo, in addition to promoting the accumulation of leukocytes, Leukotriene B.sub.4 is also a potent hyperalgesic agent and can modulate vascular permeability changes through a neutrophil dependent mechanism. Both groups of leukotrienes are formed following oxygenation of arachidonic acid through the action of a 5-lipoxygenase enzyme. See for example, Bailey, D. M., et al., Ann. Rpts. Med. Chem., 17, 203 (1982).
The leukotrienes are potent spasmogens of human trachea, bronchus and lung parenchymal strips, and when administered to normal volunteers as aerosols are 3,800 times more potent than histamine at inducing a 50% decrease in air flow at 30% of vital capacity. They mediate increases in vascular permeability in animals and promote mucous production in human bronchial explants. In addition, Leukotriene B.sub.4 may also mediate mucous production and could be an important mediator of neutrophil and eosinophil accumulation in asthmatic lungs.
In vitro studies have shown that antigen challenge of human lung results in the release of leukotrienes and in addition purified human mast cells can produce substantial amounts of leukotrienes. There is therefore good evidence that the leukotrienes are important mediators of human asthma.
Psoriasis is a human skin disease which affects between two and six percent of the population. There is no adequate therapy for psoriasis or related skin conditions. One of the earliest events in the development of prepapillary lesions is the recruitment of leukocytes to the skin site. Thus, it is postulated that one or more of the leukotrienes is involved in these diseases.
Leukotriene antagonists may also be used to treat or prevent mammalian (especially human) disease states such as erosive gastritis; erosive esophagitis; inflammatory bowel disease; ethanol-induced hemorrhagic erosions; hepatic ischemia; noxious agent induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CCl.sub.4 and D-galactosamine; ischemic renal failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced renal failure.
A general method for making the compounds of Formula I and the leukotriene antagonist activity of the compounds is described in EP No. 104,885, published Apr. 4, 1984. Since there are two asymmetric atoms in the compounds of Formula I, following the general method of the above patent application results in the formation of two diastereomers, each consisting of a racemate. In the application cited above, racemic compounds are resolved by a very difficult chromatographic separation step so that the pure enantiomers can be prepared. Moreover, the racemic diasteriomers consist of one racemate which is often much more active as a leukotriene antagonist than the other one and the same is true of the two enantiomers of each racemic diasteriomer. Furthermore, the less active diasteriomer and enantiomer generally possesses the same intrinsic toxicity as the more active diasteriomer and enantioner. In addition, it can be demonstrated that the less active diasteriomer or enantiomer depresses the antagonist activity of the active diasteriomer or enantiomer at the tissue level. Thus, for three reasons it is advantageous to use the pure, more active diasteriomer or enantiomer rather than the mixed diasteriomer or racemate.
The present invention provides improved stereoselective methods of preparing the compounds of Formula I whereby the active, more desired diasteriomer is produced essentially free of the less active undesired diasteriomer. Thus, the present invention provides new and unexpected methods which greatly improve the yield of the desired product and avoids the very difficult chromatographic separation step shown in the patent application cited above.
Additionally, the present invention provides novel intermediates which are useful in improved stereoselective methods of preparing the compounds of Formula I. The use of certain of these novel intermediates leads to final product leukotriene antagonists in greater yield and at reduced cost. Moreover, among the numerous advantages over the prior art, the use of these novel intermediates results unexpectedly in a higher ratio of the active, desired diasteriomer to the less active, undesired diasteriomer than by use of prior art intermediates.